Finnish Disease Heritage
The Finnish disease heritage is a good example of how founder
effects and genetic isolation have moulded the gene pool of this population.
A group of 36 monogenic diseases are more frequent in Finland than in any
other population. Several bottlenecks during population history and inhabitation
of remote areas in the large country by small groups of settlers has caused
enrichment of some disease causing genes and losses of others. Most of the
diseases have an autosomal recessive mode of inheritance, while two are
autosomal dominant and two X-chromosomal. Recent genetic studies have determined
the gene involved and causative mutations for 35 diseases; one founder mutation
accounts for 70 to 100 percent of these disease alleles.
Perheentupa’s steps. The timescale shows the year of first Finnish
publication of the disease.
|Finnish Population History and Diseases
The demographic history of Finland is typical of many founder
populations. A small number of original settlers, subsequent
isolation, rapid expansion, and population bottlenecks have allowed
genetic drift to mould the gene pool. The vast majority of the
Finns descend from two migrations occurring about 4,000 and 2,000
years ago. The earlier event involved eastern Uralic speakers, and
the later, Indo-European speakers from the south. Both Y-chromosomal
haplotypes and mitochondrial sequences display the low genetic
diversity among Finns compared with other European populations, and
confirm the isolation. The estimates of size of the founding
population varies from 3,000-24,000, but as late as the 12th
century, the population of Finland was only about 50,000, as
illustrated in the top figure. It reached 400,000 by the mid-17th
century, only to experience the great famine of 1696–1698,
where one third of the population perished. Since then, the Finnish
population has grown relatively rapidly from 250,000 at the
beginning of the 18th century to its present figure of 5,400,000.
Starting in the 16th century, during the reign of the Swedish King
Gustavus of Vasa (1523–1560), internal migrations created
regional subisolates (as illustrated in the bottom figure). The
subisolates in the late settlement region were established mainly by
groups of farmers originating from a small area of South Savo in
southeastern Finland. They moved to the central, then western, and
finally northern parts of the country, clearing the land by fire.
Within a century, the inhabited land area of Finland doubled. Until
the Second World War, many of these northeastern settlements grew
rapidly without further immigration to supplement the descendants
of their 40–60 founding families. The reign of Gustavus of
Vasa also established a national system of population records, an
important resource for later genetic studies of the Finns. Utilizing
these records, individuals can be traced to common ancestors,
especially in the subisolates of the late settlement region.
Finland's demographic history has led to a unique spectrum of
genetic diseases. Around 30, mostly recessive diseases, are highly
enriched in Finland. Other diseases, such as phenylketonuria and
cystic fibrosis, are almost non-existent. Molecular studies have
exposed one major mutation (70–100% alleles) in most Finnish
Mendelian diseases and revealed long genetic intervals of linkage
disequilibrium (LD) flanking the disease gene, with the length of
the LD interval reflecting the age of the mutation.
This figure originally appeared in Peltonen L et al., Nature Reviews
Genetics 1, 182-190 (2000).
Regional Distribution of the Diseases
The population history of Finland has led to an uneven
regional distribution of the disease alleles. Internal movement in the last
few decades has somewhat reduced this effect, but birthplaces of the patients’
grandparents represent a typical regional clustering (Norio R, 2003a).
This phenomenon has especially been studied in autosomal
recessive disorders. For most diseases birthplaces are concentrated around
the area of late settlement, populated from the 1500s. The example given
in the figure 3 is the distribution in Mulibrey nanism (MUL). The other
diseases in this group are APECED,
In the second group of diseases and the places of origin
are distributed throughout the country, although some clustering can be
seen in the late settlement area. This group is comprised of the most common
diseases; CHH (see figure 4), AGU, CNF, CLN1, and EPM1.
In the third group the distribution is predominantly in
the western early settlement area, and follows the population density of
Finland. This may suggest that these disease alleles have spread without
the effect of “late settlement”. This group consists of only
two disorders, which are also quite common in other parts of Europe. The
example given in the figure 5 is Meckel syndrome (MKS), and the other disease
is diastrophic dysplasia (DTD).
The fourth group consists of two diseases that are strictly
local, for which disease causing mutations have occured more recently. Northern
epilepsy (EPMR) is found in the Kainuu region near the Eastern border, and
the Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5)
in Southern Ostrobothnia.
Four autosomal recessive disorders, MEB, PEHO, RAPADILINO,
and MGA1, form the fifth “atypical” group. The distribution
of them does not overlap with the other diseases.
The two autosomal dominant (FAF, TMD) and two X-chromosomal
(CHM, RS) disorders are also regionally concentrated. They haven’t
been placed in these groups because they don’t need isolation to occur.
Geographic Distribution of Diseases
Fig. 4 Mulibrey nanism (MUL). Map by Reijo Norio,
Otava, Helsinki, 2000.
Fig. 5 Cartilage-hair hypoplasia (CHH). Map by Reijo
Suomi-neidon geenit. Otava, Helsinki, 2000.
Fig. 6 Meckel syndrome (MKS). Map by Reijo Norio,
Otava, Helsinki, 2000.
Fig. 7 Northern epilepsy (EPMR). Map by Reijo Norio, Suomi-neidon
geenit. Otava, Helsinki, 2000.
de la Chapelle A et al. Linkage disequilibrium mapping in
isolated populations: the example of Finland revisited. Proc Natl Acad Sci
USA. 1998 Oct 13;95(21):12416-23.
Kere J. Human population genetics: lessons from Finland. Annu
Rev Genomics Hum Genet. 2001;2:103-28.
Norio R. Finnish Disease Heritage I: characteristics, causes,
background. Hum Genet. 2003 May;112(5-6):441-56.
Norio R. Finnish Disease Heritage II: population prehistory
and genetic roots of Finns. Hum Genet. 2003 May;112(5-6):457-69.
Norio R. The Finnish Disease Heritage III: the individual
diseases. Hum Genet. 2003 May;112(5-6):470-526.
Peltonen L et al., Molecular genetics of the Finnish disease heritage. Hum
Mol Genet. 1999;8(10):1913-23.